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Updated: Dec 7, 2025
Measurements of Physiological Stress Responses in C. Elegans
Published on: May 21, 2020
High-throughput small molecule screening reveals Nrf2-dependent and -independent pathways of cellular stress
David B Lombard1,2, William J Kohler3, Angela H Guo3
1Department of Pathology, University of Michigan, Ann Arbor, MI, USA. davidlom@med.umich.edu.
Abstract:
Aging is the dominant risk factor for most chronic diseases. Development of antiaging interventions offers the promise of preventing many such illnesses simultaneously. Cellular stress resistance is an evolutionarily conserved feature of longevity. Here, we identify compounds that induced resistance to the superoxide generator paraquat (PQ), the heavy metal cadmium (Cd), and the DNA alkylator methyl methanesulfonate (MMS). Some rescue compounds conferred resistance to a single stressor, while others provoked multiplex resistance. Induction of stress resistance in fibroblasts was predictive of longevity extension in a published large-scale longevity screen in Caenorhabditis elegans, although not in testing performed in worms and flies with a more restricted set of compounds. Transcriptomic analysis and genetic studies implicated Nrf2/SKN-1 signaling in stress resistance provided by two protective compounds, cardamonin and AEG 3482. Small molecules identified in this work may represent attractive tools to elucidate mechanisms of stress resistance in mammalian cells.
Insights
Researchers identified compounds that enhance cellular stress resistance, a key factor in longevity. These compounds may help prevent age-related diseases by improving the body
Area of Science:
- Gerontology and cellular biology
- Molecular mechanisms of aging and stress response
Background:
- Aging is a primary risk factor for numerous chronic diseases.
- Cellular stress resistance is a conserved mechanism linked to longevity.
- Developing interventions that target aging could simultaneously prevent multiple diseases.
Purpose of the Study:
- To identify compounds that confer resistance to various cellular stressors.
- To investigate the relationship between induced stress resistance and longevity.
- To elucidate the molecular pathways involved in compound-mediated stress resistance.
Main Methods:
- Screening compounds for resistance to paraquat (PQ), cadmium (Cd), and methyl methanesulfonate (MMS).
- Testing compound efficacy in mammalian fibroblasts and in model organisms (C. elegans, flies).
- Utilizing transcriptomic analysis and genetic studies to identify signaling pathways.
Main Results:
- Identified compounds that induced single or multiplex stress resistance in fibroblasts.
- Observed a correlation between fibroblast stress resistance and longevity extension in C. elegans.
- Nrf2/SKN-1 signaling pathway implicated in the protective effects of cardamonin and AEG 3482.
Conclusions:
- Small molecules can induce cellular stress resistance, potentially impacting longevity.
- Nrf2/SKN-1 signaling plays a role in mediating these protective effects.
- Identified compounds serve as valuable tools for studying stress resistance mechanisms.
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